There is an increasingly pressing need for methods to permit more objective, precise, and systematic assessment of patients with Post- traumatic Stress Disorder (PTSD), as the prevalence and clinical importance of this disorder is becoming more widely recognized. Because the clinical presentation of patients with PTSD can often be complex and varied there is a particular need for innovative methods to increase specificity in the definition and differential diagnosis of this disorder. As yet, there has been very little exploration of biological approaches to the characterization and the understanding of PTSD and its underlying mechanisms. We have been evaluating an innovative multidimensional hormonal approach to the assessment of PTSD in contrast to the conventional univariate approach focussing on one biological marker at a time in psychiatric patients. We have obtained pilot data with a profile of hormones, including cortisol, norepinephrine, epinephrine, testosterone, and thyroxine, in PTSD inpatients in comparison with 4 other inpatients groups: Major depressive disorder, endogenous; Bipolar I, manic; Paranoid schizophrenia; and Undifferentiated schizophrenia. We have found a very unusual dissociation between the cortisol and norepinephrine systems in PTSD, with sustained high urinary norepinephrine levels in the face of low urinary free-cortisol levels. As a results, the mean ration (norepinephrine/corticol) is about twice as high in PTSD as in all the other diagnostic groups, with a diagnostic sensitivity of 78% and specificity of 94%. Moving from a bivariate to a multivariate approach with 3 or more hormones, we found that Stepwise Discriminant Analysis provided 100% correct diagnostic classification of PTSD versus Major depressive disorder and that Multidimensional Scaling classified all but one patient out of 17 correctly in comparing these two diagnostic groups. These findings indicate that multidimensional hormonal assessment provides the promise of important advances in the use of biological criteria in psychiatric diagnosis and that this approach may be particularly useful in the investigation of PTSD.